It is a standard practice to treat diabetes mellitus predominately with injections of insulin to counter the inability of the pancreas to manufacture and secrete insulin in response to elevated blood glucose levels. For optimal therapy, it is necessary to determine the glucose concentration in the body in order to specify the appropriate amount and time of the antidiabetes medication. This requires a glucose sensing device, which may be most effective if implanted in the body.
One approach to the development of an implantable sensor is the so-called enzyme electrode in which an immobilized enzyme catalyzes a chemical reaction between glucose and another molecule such as oxygen that can be detected by an electrode. The enzymatic reaction is one in which glucose is catalytically converted to gluconic acid with the simultaneous consumption of oxygen promoted by the enzyme glucose oxidase, with the resulting decrease in oxygen determined by an amperometric oxygen electrode and thereby related to glucose levels. A key problem in developing this sensor is that the glucose concentration in the body is normally higher than the oxygen concentration by a factor of 50-1000 times. Thus, since the enzymatic reaction is limited by oxygen, the least abundant reactant, glucose measurements in the body are often inaccurate. Most previous investigators have not recognized or gone beyond this problem.
Hicks et al. in U.S. Pat. No. 3,542,662 describe an electrolytic glucose sensor capable of assaying glucose in fluid removed from the body, but not usable for measuring glucose directly in vivo. Hicks et al. describe an enzyme-containing membrane disposed between a fluid being assayed and first oxygen sensor electrode and a similar membrane not containing enzymes disposed between a fluid and second reference oxygen electrode. Oxygen diffuses through the enzyme-containing membrane and is consumed in an equal molar reaction with glucose catalyzed by the enzyme glucose oxidase; consequently, oxygen is unavailable for detection by the oxygen sensor electrode. The second oxygen sensor electrode measures the concentration of oxygen existing absent any enzyme-catalyzed reaction. The difference in oxygen levels detected by the two electrodes is proportional to the glucose concentration within certain limits.
The glucose sensor described by Hicks et al. performs satisfactorily when assaying for glucose in vitro. However, when the sensor is used directly in the body, its performance is unreliable. In part, this appears to be due to the inability of the dual-sensor design to function adequately in low-oxygen environments.
Presently there does not exist an implantable sensor suitable for detecting glucose in regions of the body where oxygen concentrations are lower than glucose concentrations. Previously, however, Fisher and Abel in "A Membrane Combination for Implantable Glucose Sensors, Measurements in Undiluted Biological Fluids" (Trans. Am. Soc. Artif. Intern. Organs, Vol. XXVIII, 1982) have attempted to solve the problem by positioning sandwich membrane in association with an oxygen electrode sensor. The membranes consist of a hydrophobic layer over an enzyme layer, with the former having a minute hole aligned with the oxygen electrode sensor so as to allow predominately access of glucose from the fluid being assayed. The hydrophobic layer was selected to be permeable predominantly to oxygen; consequently, oxygen diffused into the enzyme layer at all points across the surface of the hydrophobic layer whereas glucose diffused in only at the region of the hole. In this manner, a stoichiometric excess of oxygen over glucose was provided to the enzyme layer. As a result of the requirement that glucose entry be restricted to a small opening in the hydrophobic membrane, this oxygen electrode sensor apparatus is limited as to the range of concentrations of glucose detectable. Also, because the enzyme situated near the opening in the hydrophobic membrane is constantly exposed to incoming glucose, it tends to become inactivated, which in turn requires that for the sensor to continue functioning glucose must diffuse further into the membrane, which additionally limits the use of the sensor in that it increases its response time.